DESCRIPTION

Adalat® CC is an extended release tablet dosage form of
the calcium channel blocker nifedipine. Nifedipine is 3,5-pyridinedicarboxylic
acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-dimethyl ester, C17H18N2O6,
and has the structural formula:

Nifedipine is a yellow crystalline substance, practically
insoluble in water but soluble in ethanol. It has a molecular weight of 346.3.
Adalat CC tablets consist of an external coat and an internal core. Both contain
nifedipine, the coat as a slow release formulation and the core as a fast
release formulation. Adalat CC tablets contain either: 30, 60, or 90 mg of
nifedipine for once-a-day oral administration.

INDICATIONS

DOSAGE AND ADMINISTRATION

Dosage should be adjusted according to each patient's
needs. It is recommended that Adalat CC be administered orally once daily on an
empty stomach. Adalat CC is an extended release dosage form and tablets should
be swallowed whole, not bitten or divided. In general, titration should proceed
over a 7- 14 day period starting with 30 mg once daily. Upward titration should
be based on therapeutic efficacy and safety. The usual maintenance dose is 30
mg to 60 mg once daily. Titration to doses above 90 mg daily is not
recommended.

If discontinuation of Adalat CC is necessary, sound
clinical practice suggests that the dosage should be decreased gradually with
close physician supervision.

SIDE EFFECTS

Adverse Experiences

The incidence of adverse events during treatment with
Adalat CC in doses up to 90 mg daily were derived from multi-center
placebo-controlled clinical trials in 370 hypertensive patients. Atenolol 50 mg
once daily was used concomitantly in 187 of the 370 patients on Adalat CC and
in 64 of the 126 patients on placebo. All adverse events reported during Adalat
CC therapy were tabulated independently of their causal relationship to
medication.

The most common adverse event reported with Adalat CC was
peripheral edema. This was dose related and the frequency was 18% on Adalat CC
30 mg daily, 22% on Adalat CC 60 mg daily and 29% on Adalat CC 90 mg daily
versus 10% on placebo.

Other common adverse events reported in the above
placebo-controlled trials include:

Adverse Event

ADALAT CC (%)
(n=370)

PLACEBO(%)
(n=126)

Headache

19

13

Flushing/heat sensation

4

0

Dizziness

4

2

Fatigue/asthenia

4

4

Nausea

2

1

Constipation

1

0

Where the frequency of adverse events with Adalat CC and
placebo is similar, causal relationship cannot be established.

The following adverse events were reported with an
incidence of 3% or less in daily doses up to 90 mg:

DRUG INTERACTIONS

Nifedipine is mainly eliminated by metabolism and is a
substrate of CYP3A. Inhibitors and inducers of CYP3A can impact the exposure to
nifedipine and consequently its desirable and undesirable effects. In vitro and
in vivo data indicate that nifedipine can inhibit the metabolism of drugs that
are substrates of CYP3A, thereby increasing the exposure to other drugs.
Nifedipine is a vasodilator, and coadministration of other drugs affecting
blood pressure may result in pharmacodynamic interactions.

CYP3A Inhibitors

CYP3A inhibitors such as ketoconazole, fluconazole,
itraconazole, clarithromycin, erythromycin (Azithromycin, although structurally
related to the class of macrolide antibiotic is void of clinically relevant
CYP3A4 inhibition), grapefruit, nefazodone, fluoxetine, saquinavir, indinavir,
nelfinavir, and ritonavir may result in increased exposure to nifedipine when
co-administered. Careful monitoring and dose adjustment may be necessary;
consider initiating nifedipine at the lowest dose available if given concomitantly
with these medications.

Strong CYP3A Inducers

Strong CYP3A inducers, such as rifampin, rifabutin,
phenobarbital, phenytoin, carbamazepine, and St. John's Wort reduce the
bioavailability and efficacy of nifedipine; therefore nifedipine should not be used
in combination with strong CYP3A inducers such as rifampin (SeeCONTRAINDICATIONS).

Cardiovascular Drugs

Antiarrhythmics

Quinidine: Quinidine is a substrate of CYP3A and
has been shown to inhibit CYP3A in vitro. Coadministration of multiple doses of
quinidine sulfate, 200 mg t.i.d., and nifedipine, 20 mg t.i.d., increased Cmax
and AUC of nifedipine in healthy volunteers by factors of 2.30 and 1.37,
respectively. The heart rate in the initial interval after drug administration
was increased by up to 17.9 beats/minute. The exposure to quinidine was not
importantly changed in the presence of nifedipine. Monitoring of heart rate and
adjustment of the nifedipine dose, if necessary, are recommended when quinidine
is added to a treatment with nifedipine.

Flecainide: There has been too little experience
with the co-administration of Tambocor with nifedipine to recommend concomitant
use.

Calcium Channel Blockers

Diltiazem: Pre-treatment of healthy volunteers
with 30 mg or 90 mg t.i.d. diltiazem p.o. increased the AUC of nifedipine after
a single dose of 20 mg nifedipine by factors of 2.2 and 3.1, respectively. The corresponding
Cmax values of nifedipine increased by factors of 2.0 and 1.7, respectively.
Caution should be exercised when co-administering diltiazem and nifedipine and
a reduction of the dose of nifedipine should be considered.

Verapamil: Verapamil, a CYP3A inhibitor, can
inhibit the metabolism of nifedipine and increase the exposure to nifedipine
during concomitant therapy. Blood pressure should be monitored and reduction of
the dose of nifedipine considered.

ACE Inhibitors

Benazepril: In healthy volunteers receiving single
dose of 20 mg nifedipine ER and benazepril 10 mg, the plasma concentrations of
benazeprilat and nifedipine in the presence and absence of each other were not
statistically significantly different. A hypotensive effect was only seen after
co-administration of the two drugs. The tachycardic effect of nifedipine was
attenuated in the presence of benazepril.

Angiotensin-II Blockers

Irbesartan:In vitro studies show significant
inhibition of the formation of oxidized irbesartan metabolites by nifedipine.
However, in clinical studies, concomitant nifedipine had no effect on irbesartan
pharmacokinetics.

Candesartan: No significant drug interaction has
been reported in studies with candesartan cilexitil given together with
nifedipine. Because candesartan is not significantly metabolized by the
cytochrome P450 system and at therapeutic concentrations has no effect on
cytochrome P450 enzymes, interactions with drugs that inhibit or are
metabolized by those enzymes would not be expected.

Beta-blockers

Adalat CC was well tolerated when administered in
combination with beta-blockers in 187 hypertensive patients in a
placebo-controlled clinical trial. However, there have been occasional
literature reports suggesting that the combination nifedipine and
beta-adrenergic blocking drugs may increase the likelihood of congestive heart
failure, severe hypotension or exacerbation of angina in patients with cardiovascular
disease. Clinical monitoring is recommended and a dose adjustment of nifedipine
should be considered.

Timolol: Hypotension is more likely to occur if
dihydropryridine calcium antagonists such as nifedipine are co-administered
with timolol.

Central Alpha1-Blockers

Doxazosin: Healthy volunteers participating in a
multiple dose doxazosin-nifedipine interaction study received 2 mg doxazosin
q.d. alone or combined with 20 mg nifedipine ER b.i.d. Co-administration of nifedipine
resulted in a decrease in AUC and Cmax of doxazosin to 83% and 86% of the
values in the absence of nifedipine, respectively. In the presence of
doxazosin, AUC and Cmax of nifedipine were increased by factors of 1.13 and
1.23, respectively. Compared to nifedipine monotherapy, blood pressure was
lower in the presence of doxazosin. Blood pressure should be monitored when
doxazosin is co-administered with nifedipine, and dose reduction of nifedipine
considered.

Digitalis

Digoxin: The simultaneous administration of
nifedipine and digoxin may lead to reduced clearance resulting in an increase
in plasma concentrations of digoxin. Since there have been isolated reports of patients
with elevated digoxin levels, and there is a possible interaction between
digoxin and Adalat CC, it is recommended that digoxin levels be monitored when
initiating, adjusting and discontinuing Adalat CC to avoid possible over- or
under- digitalization.

Antithrombotics

Coumarins: There have been rare reports of
increased prothrombin time in patients taking coumarin anticoagulants to whom
nifedipine was administered. However the relationship to nifedipine therapy is uncertain.

Platelet Aggregation Inhibitors

Clopidogrel: No clinically significant
pharmacodynamic interactions were observed when clopidrogrel was
co-administered with nifedipine.

Tirofiban: Co-administration of nifedipine did not
alter the exposure to tirofiban importantly.

Other

Non-Cardiovascular Drugs

Antifungal Drugs

Ketoconazole, itraconazole and fluconazole are CYP3A
inhibitors and can inhibit the metabolism of nifedipine and increase the
exposure to nifedipine during concomitant therapy. Blood pressure should be
monitored and a dose reduction of nifedipine considered.

Antisecretory Drugs

Omeprazole: In healthy volunteers receiving a
single dose of 10 mg nifedipine, AUC and Cmax of nifedipine after pretreatment
with omeprazole 20 mg q.d. for 8 days were 1.26 and 0.87 times those after
pre-treatment with placebo. Pretreatment with or co-administration of
omeprazole did not impact the effect of nifedipine on blood pressure or heart
rate. The impact of omeprazole on nifedipine is not likely to be of clinical
relevance.

Pantoprazole: In healthy volunteers the exposure
to neither drug was changed significantly in the presence of the other drug.

Ranitidine: Five studies in healthy volunteers
investigated the impact of multiple ranitidine doses on the single or multiple
dose pharmacokinetics of nifedipine. Two studies investigated the impact of
coadministered ranitidine on blood pressure in hypertensive subjects on
nifedipine. Co-administration of ranitidine did not have relevant effects on
the exposure to nifedipine that affected the blood pressure or heart rate in
normotensive or hypertensive subjects.

Cimetidine: Five studies in healthy volunteers
investigated the impact of multiple cimetidine doses on the single or multiple
dose pharmacokinetics of nifedipine. Two studies investigated the impact of
coadministered cimetidine on blood pressure in hypertensive subjects on
nifedipine. In normotensive subjects receiving single doses of 10 mg or
multiple doses of up to 20 mg nifedipine t.i.d. alone or together with
cimetidine up to 1000 mg/day, the AUC values of nifedipine in the presence of
cimetidine were between 1.52 and 2.01 times those in the absence of cimetidine.
The Cmax values of nifedipine in the presence of cimetidine were increased by
factors ranging between 1.60 and 2.02. The increase in exposure to nifedipine
by cimetidine was accompanied by relevant changes in blood pressure or heart rate
in normotensive subjects. Hypertensive subjects receiving 10 mg q.d. nifedipine
alone or in combination with cimetidine 1000 mg q.d. also experienced relevant
changes in blood pressure when cimetidine was added to nifedipine. The
interaction between cimetidine and nifedipine is of clinical relevance and
blood pressure should be monitored and a reduction of the dose of nifedipine
considered.

Cisapride: Simultaneous administration of cisapride
and nifedipine may lead to increased plasma concentrations of nifedipine.

Antibacterial Drugs

Quinupristin/Dalfopristin:In vitro drug
interaction studies have demonstrated that quinupristin/dalfopristin significantly
inhibits the CYP3A metabolism of nifedipine. Concomitant administration of quinupristin/dalfopristin
and nifedipine (repeated oral dose) in healthy volunteers increased AUC and Cmax
for nifedipine by factors of 1.44 and 1.18, respectively, compared to
nifedipine monotherapy. Upon co-administration of quinupristin/dalfopristin
with nifedipine, blood pressure should be monitored and a reduction of the dose
of nifedipine considered.

Erythromycin: Erythromycin, a CYP3A inhibitor, can
inhibit the metabolism of nifedipine and increase the exposure to nifedipine
during concomitant therapy. Blood pressure should be monitored and reduction of
the dose of nifedipine considered.

Antitubercular Drugs

Rifampin: Strong CYP3A inducers, such as rifampin,
rifapentin, and rifabutin reduce the bioavailability of nifedipine which may
reduce the efficacy of nifedipine; therefore nifedipine should not be used in combination
with strong CYP3A inducers such as rifampin (See CONTRAINDICATIONS). The
impact of multiple oral doses of 600 mg rifampin on the pharmacokinetics of
nifedipine after a single oral dose of 20 mg nifedipine capsule was evaluated
in a clinical study. Twelve healthy male volunteers received a single oral dose
of 20 mg nifedipine capsule on study Day 1. Starting on study Day 2, the subjects
received 600 mg rifampin once daily for 14 days. On study Day 15, a second
single oral dose of 20 mg nifedipine capsule was administered together with the
last dose of rifampin. Compared to study Day 1, 14 days pretreatment with
rifampin reduced Cmax and AUC of concomitantly administered nifedipine on
average by 95% and 97%, respectively.

Antiviral Drugs

Amprenavir, atanazavir, delavirine, fosamprinavir,
indinavir, nelfinavir and ritonavir, as CYP3A inhibitors, can
inhibit the metabolism of nifedipine and increase the exposure to nifedipine.
Caution is warranted and clinical monitoring of patients recommended.

CNS Drugs

Nefazodone, a CYP3A inhibitor, can inhibit
the metabolism of nifedipine and increase the exposure to nifedipine during
concomitant therapy. Blood pressure should be monitored and a reduction of the
dose of nifedipine considered.

Fluoxetine, a CYP3A inhibitor, can inhibit the
metabolism of nifedipine and increase the exposure to nifedipine during
concomitant therapy. Blood pressure should be monitored and a reduction of the
dose of nifedipine considered.

Valproic acid may increase the exposure to
nifedipine during concomitant therapy. Blood pressure should be monitored and a
dose reduction of nifedipine considered.

Phenytoin, Phenobarbital, and Carbamazepine: Nifedipine
is metabolized by CYP3A. Co-administration of nifedipine 10 mg capsule and 60
mg nifedipine coat-core tablet with phenytoin, an inducer of CYP3A, lowered the
AUC and Cmax of nifedipine by approximately 70%. Phenobarbital and carbamazepine
are also inducers of CYP3A. Alternative antihypertensive therapy should be
considered in patients taking phenytoin, phenobarbital, and carbamazepine.

Antiemetic Drugs

Dolasetron: In patients taking dolasetron by the
oral or intravenous route and nifedipine, no effect was shown on the clearance
of hydrodolasetron.

Immunosuppressive Drugs

Tacrolimus: Tacrolimus has been shown to be
metabolized via the CYP3A system. Nifedipine has been shown to inhibit the
metabolism of tacrolimus in vitro. Transplant patients on tacrolimus and
nifedipine required from 26% to 38% smaller doses than patients not receiving
nifedipine. Nifedipine can increase the exposure to tacrolimus. When nifedipine
is co-administered with tacrolimus the blood concentrations of tacrolimus should
be monitored and a reduction of the dose of tacrolimus considered.

Sirolimus: A single 60 mg dose of nifedipine and a
single 10 mg dose of sirolimus oral solution were administered to 24 healthy
volunteers. Clinically significant pharmacokinetic drug interactions were not observed.

Glucose Lowering Drugs

Pioglitazone: Co-administration of pioglitazone
for 7 days with 30 mg nifedipine ER administered orally q.d. for 4 days to male
and female volunteers resulted in least square mean (90% CI) values for unchanged
nifedipine of 0.83 (0.73-0.95) for Cmax and 0.88 (0.80-0.96) for AUC relative
to nifedipine monotherapy. In view of the high variability of nifedipine
pharmacokinetics, the clinical significance of this finding is unknown.

Rosiglitazone: Co-administration of rosiglitazone
(4 mg b.i.d.) was shown to have no clinically relevant effect on the
pharmacokinetics of nifedipine.

Metformin: A single dose metformin-nifedipine
interaction study in normal healthy volunteers demonstrated that co-administration
of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%,
respectively, and increased the amount of metformin excreted in urine. Tmax and
half-life were unaffected. Nifedipine appears to enhance the absorption of
metformin.

Miglitol: No effect of miglitol was observed on
the pharmacokinetics and pharmacodynamics of nifedipine.

Repaglinide: Co-administration of 10 mg nifedipine
with a single dose of 2 mg repaglinide (after 4 days nifedipine 10 mg t.i.d.
and repaglinide 2 mg t.i.d.) resulted in unchanged AUC and Cmax values for both
drugs.

Acarbose: Nifedipine tends to produce
hyperglycemia and may lead to loss of glucose control. If nifedipine is
co-administered with acarbose, blood glucose levels should be monitored
carefully and a dose adjustment of nifedipine considered.

Drugs Interfering with Food Absorption

Dietary Supplements

Grapefruit Juice: In healthy volunteers, a single
dose co-administration of 250 mL double strength grapefruit juice with 10 mg
nifedipine increased AUC and Cmax by factors of 1.35 and 1.13, respectively.
Ingestion of repeated doses of grapefruit juice (5 x 200 mL in 12 hours) after administration
of 20 mg nifedipine ER increased AUC and Cmax of nifedipine by a factor of 2. Grapefruit
juice should be avoided by patients on nifedipine. The intake of grapefruit
juice should be stopped at least 3 days prior to initiating patients on
nifedipine.

Herbals

St. John's Wort: St. John's Wort is an inducer of
CYP3A and may decrease exposure to nifedipine. Alternative antihypertensive
therapy should be considered in patients in whom St. John's Wort therapy is
necessary.

CYP2D6 Probe Drug

Debrisoquine: In healthy volunteers, pretreatment
with nifedipine 20 mg t.i.d. for 5 days did not change the metabolic ratio of
hydroxydebrisoquine to debrisoquine measured in urine after a single dose of 10
mg debrisoquine. Thus, it is improbable that nifedipine inhibits in vivo the
metabolism of other drugs that are substrates of CYP2D6.

WARNINGS

Excessive Hypotension

Although in most patients the hypotensive effect of
nifedipine is modest and well tolerated, occasional patients have had excessive
and poorly tolerated hypotension. These responses have usually occurred during
initial titration or at the time of subsequent upward dosage adjustment, and
may be more likely in patients using concomitant beta-blockers.

Severe hypotension and/or increased fluid volume
requirements have been reported in patients who received immediate release
capsules together with a beta-blocking agent and who underwent coronary artery
bypass surgery using high dose fentanyl anesthesia. The interaction with high
dose fentanyl appears to be due to the combination of nifedipine and a
beta-blocker, but the possibility that it may occur with nifedipine alone, with
low doses of fentanyl, in other surgical procedures, or with other narcotic
analgesics cannot be ruled out. In nifedipine-treated patients where surgery
using high dose fentanyl anesthesia is contemplated, the physician should be
aware of these potential problems and, if the patient's condition permits,
sufficient time (at least 36 hours) should be allowed for nifedipine to be washed
out of the body prior to surgery.

Increased Angina And/Or Myocardial Infarction

Rarely, patients, particularly those who have severe
obstructive coronary artery disease, have developed well-documented increased
frequency, duration and/or severity of angina or acute myocardial infarction
upon starting nifedipine or at the time of dosage increase. The mechanism of
this effect is not established.

Beta-Blocker Withdrawal

When discontinuing a beta-blocker it is important to
taper its dose, if possible, rather than stopping abruptly before beginning
nifedipine. Patients recently withdrawn from beta blockers may develop a withdrawal
syndrome with increased angina, probably related to increased sensitivity to
catecholamines. Initiation of nifedipine treatment will not prevent this occurrence
and on occasion has been reported to increase it.

Congestive Heart Failure

Rarely, patients (usually while receiving a beta-blocker)
have developed heart failure after beginning nifedipine. Patients with tight
aortic stenosis may be at greater risk for such an event, as the unloading effect
of nifedipine would be expected to be of less benefit to these patients, owing
to their fixed impedance to flow across the aortic valve.

PRECAUTIONS

General

Hypotension

Because nifedipine decreases peripheral vascular
resistance, careful monitoring of blood pressure during the initial
administration and titration of Adalat CC is suggested. Close observation is
especially recommended for patients already taking medications that are known
to lower blood pressure (See WARNINGS).

Peripheral Edema

Mild to moderate peripheral edema occurs in a
dose-dependent manner with Adalat CC. The placebo subtracted rate is
approximately 8% at 30 mg, 12% at 60 mg and 19% at 90 mg daily. This edema is a
localized phenomenon, thought to be associated with vasodilation of dependent
arterioles and small blood vessels and not due to left ventricular dysfunction
or generalized fluid retention. With patients whose hypertension is complicated
by congestive heart failure, care should be taken to differentiate this peripheral
edema from the effects of increasing left ventricular dysfunction.

Use In Cirrhotic Patients

Clearance of nifedipine is reduced and systemic exposure
increased in patients with cirrhosis. It is unknown how systemic exposure may
be altered in patients with moderate or severe liver impairment. Careful
monitoring and dose reduction may be necessary; consider initiating therapy
with the lowest dose available.

Laboratory Tests

Rare, usually transient, but occasionally significant
elevations of enzymes such as alkaline phosphatase, CPK, LDH, SGOT, and SGPT
have been noted. The relationship to nifedipine therapy is uncertain in most
cases, but probable in some. These laboratory abnormalities have rarely been
associated with clinical symptoms; however, cholestasis with or without
jaundice has been reported. A small increase ( < 5%) in mean alkaline
phosphatase was noted in patients treated with Adalat CC. This was an isolated finding
and it rarely resulted in values which fell outside the normal range. Rare
instances of allergic hepatitis have been reported with nifedipine treatment.
In controlled studies, Adalat CC did not adversely affect serum uric acid,
glucose, cholesterol or potassium.

Nifedipine, like other calcium channel blockers,
decreases platelet aggregationin vitro. Limited clinical studies have
demonstrated a moderate but statistically significant decrease in platelet
aggregation and increase in bleeding time in some nifedipine patients. This is
thought to be a function of inhibition of calcium transport across the platelet
membrane. No clinical significance for these findings has been demonstrated.

Positive direct Coombs' test with or without hemolytic anemia has been reported but a causal relationship between nifedipine
administration and positivity of this laboratory test, including hemolysis, could
not be determined.

Although nifedipine has been used safely in patients with
renal dysfunction and has been reported to exert a beneficial effect in certain
cases, rare reversible elevations in BUN and serum creatinine have been
reported in patients with pre-existing chronic renal insufficiency. The
relationship to nifedipine therapy is uncertain in most cases but probable in
some.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Nifedipine was administered orally to rats for two years
and was not shown to be carcinogenic. When given to rats prior to mating,
nifedipine caused reduced fertility at a dose approximately 30 times the maximum
recommended human dose. There is a literature report of reversible reduction
in the ability of human sperm obtained from a limited number of infertile men
taking recommended doses of nifedipine to bind to and fertilize an ovum in
vitro. In vivo mutagenicity studies were negative.

Pregnancy

Pregnancy Category C

In rodents, rabbits and monkeys, nifedipine has been
shown to have a variety of embryotoxic, placentotoxic, teratogenic and
fetotoxic effects, including stunted fetuses (rats, mice and rabbits), digital anomalies
(rats and rabbits), rib deformities (mice), cleft palate (mice), small
placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal
deaths (rats, mice and rabbits), prolonged pregnancy (rats; not evaluated in
other species), and decreased neonatal survival (rats; not evaluated in other
species). On a mg/kg or mg/m² basis, some of the doses associated with these various
effects are higher than the maximum recommended human dose and some are lower,
but all are within an order of magnitude of it.

The digital anomalies seen in nifedipine-exposed rabbit
pups are strikingly similar to those seen in pups exposed to phenytoin, and
these are in turn similar to the phalangeal deformities that are the most common
malformation seen in human children with in utero exposure to phenytoin.

Careful monitoring of blood pressure must be exercised in
pregnant women, when administering nifedipine in combination with IV magnesium
sulfate due to the possibility of an excessive fall in blood pressure which
could harm the mother and fetus.

There are no adequate and well-controlled studies in
pregnant women.

Nursing Mothers

Nifedipine is excreted in human milk. Nursing mothers are
advised not to breastfeed their babies when taking the drug.

Pediatric Use

The safety and effectiveness of Adalat CC in pediatric
patients have not been established.

Geriatric Use

Although small pharmacokinetic studies have identified an
increased half-life and increased Cmax and AUC (See CLINICAL PHARMACOLOGY:
Pharmacokinetics and Metabolism), clinical studies of nifedipine did not
include sufficient numbers of subjects aged 65 and over to determine whether
they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the greater
frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy.

Patients With Galactose Intolerance

Since this medicinal product contains lactose, patients
with rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption should not take this medicine.

OVERDOSE

Experience with nifedipine overdosage is limited.
Symptoms associated with severe nifedipine overdosage include loss of
consciousness, drop in blood pressure, heart rhythm disturbances, metabolic
acidosis, hypoxia, cardiogenic shock with pulmonary edema. Generally,
overdosage with nifedipine leading to pronounced hypotension calls for active
cardiovascular support including monitoring of cardiovascular and respiratory
function, elevation of extremities, judicious use of calcium infusion, pressor
agents and fluids. After oral ingestion, thorough gastric lavage is indicated,
if necessary in combination with irrigation of the small intestine. In cases
involving overdosage of a slowrelease product like nifedipine, elimination must
be as complete as possible, including from the small intestine, to prevent the
subsequent absorption of the active substance. Additional liquid or volume must
be administered with caution because of the risk of fluid overload.

Clearance of nifedipine would be expected to be prolonged
in patients with impaired liver function. Since nifedipine is highly protein
bound, dialysis is not likely to be of any benefit; however, plasmapheresis may
be beneficial.

There has been one reported case of massive overdosage
with tablets of another extended release formulation of nifedipine. The main
effects of ingestion of approximately 4800 mg of nifedipine in a young man
attempting suicide as a result of cocaine-induced depression was initial
dizziness, palpitations, flushing, and nervousness. Within several hours of
ingestion, nausea, vomiting, and generalized edema developed. No significant
hypotension was apparent at presentation, 18 hours post ingestion. Blood
chemistry abnormalities consisted of a mild, transient elevation of serum creatinine,
and modest elevations of LDH and CPK, but normal SGOT. Vital signs remained
stable, no electrocardiographic abnormalities were noted and renal function
returned to normal within 24 to 48 hours with routine supportive measures
alone. No prolonged sequelae were observed.

The effect of a single 900 mg ingestion of nifedipine
capsules in a depressed anginal patient on tricyclic antidepressants was loss
of consciousness within 30 minutes of ingestion, and profound hypotension,
which responded to calcium infusion, pressor agents, and fluid replacement. A
variety of ECG abnormalities were seen in this patient with a history of bundle
branch block, including sinus bradycardia and varying degrees of AV block.
These dictated the prophylactic placement of a temporary ventricular pacemaker,
but otherwise resolved spontaneously. Significant hyperglycemia was seen
initially in this patient, but plasma glucose levels rapidly normalized without
further treatment.

A young hypertensive patient with advanced renal failure
ingested 280 mg of nifedipine capsules at one time, with resulting marked
hypotension responding to calcium infusion and fluids. No AV conduction abnormalities,
arrhythmias, or pronounced changes in heart rate were noted, nor was there any
further deterioration in renal function.

Bradycardiac heart rhythm disturbances may be treated
symptomatically with ß-sympathomimetics, and in life-threatening bradycardiac
disturbances of heart rhythm temporary pacemaker therapy can be advisable.

CONTRAINDICATIONS

Concomitant administration with strong P450 inducers,
such as rifampin, are contraindicated since the efficacy of nifedipine tablets
could be significantly reduced. (SeeDRUG INTERACTIONS)

Nifedipine must not be used in cases of cardiogenic
shock.

Adalat is contraindicated in patients with a known
hypersensitivity to any component of the tablet.

CLINICAL PHARMACOLOGY

Nifedipine is a calcium ion influx inhibitor
(slow-channel blocker or calcium ion antagonist) which inhibits the
transmembrane influx of calcium ions into vascular smooth muscle and cardiac
muscle. The contractile processes of vascular smooth muscle and cardiac muscle
are dependent upon the movement of extracellular calcium ions into these cells
through specific ion channels. Nifedipine selectively inhibits calcium ion
influx across the cell membrane of vascular smooth muscle and cardiac muscle without
altering serum calcium concentrations.

Mechanism Of Action

The mechanism by which nifedipine reduces arterial blood
pressure involves peripheral arterial vasodilatation and, consequently, a
reduction in peripheral vascular resistance. The increased peripheral vascular
resistance, an underlying cause of hypertension, results from an increase in
active tension in the vascular smooth muscle. Studies have demonstrated that
the increase in active tension reflects an increase in cytosolic free calcium.

Nifedipine is a peripheral arterial vasodilator which
acts directly on vascular smooth muscle. The binding of nifedipine to
voltage-dependent and possibly receptor-operated channels in vascular smooth muscle
results in an inhibition of calcium influx through these channels. Stores of
intracellular calcium in vascular smooth muscle are limited and thus dependent
upon the influx of extracellular calcium for contraction to occur. The
reduction in calcium influx by nifedipine causes arterial vasodilation and decreased
peripheral vascular resistance which results in reduced arterial blood
pressure.

Pharmacokinetics And Metabolism

Nifedipine is completely absorbed after oral
administration. The bioavailability of nifedipine as Adalat CC relative to
immediate release nifedipine is in the range of 84%-89%. After ingestion of
Adalat CC tablets under fasting conditions, plasma concentrations peak at about
2.5-5 hours with a second small peak or shoulder evident at approximately 6-12
hours post dose. The elimination half-life of nifedipine administered as Adalat
CC is approximately 7 hours in contrast to the known 2 hour elimination
half-life of nifedipine administered as an immediate release capsule.

When Adalat CC is administered as multiples of 30 mg
tablets over a dose range of 30 mg to 90 mg, the area under the curve (AUC) is
dose proportional; however, the peak plasma concentration for the 90 mg dose
given as 3 x 30 mg is 29% greater than predicted from the 30 mg and 60 mg
doses.

Two 30 mg Adalat CC tablets may be interchanged with a 60
mg Adalat CC tablet. Three 30 mg Adalat CC tablets, however, result in substantially
higher Cmax values than those after a single 90 mg Adalat CC tablet. Three 30
mg tablets should, therefore, not be considered interchangeable with a 90 mg tablet.

Once daily dosing of Adalat CC under fasting conditions
results in decreased fluctuations in the plasma concentration of nifedipine
when compared to t.i.d. dosing with immediate release nifedipine capsules. The
mean peak plasma concentration of nifedipine following a 90 mg Adalat CC
tablet, administered under fasting conditions, is approximately 115 ng/mL. When
Adalat CC is given immediately after a high fat meal in healthy volunteers,
there is an average increase of 60% in the peak plasma nifedipine concentration,
a prolongation in the time to peak concentration, but no significant change in the
AUC. Plasma concentrations of nifedipine when Adalat CC is taken after a fatty
meal result in slightly lower peaks compared to the same daily dose of the
immediate release formulation administered in three divided doses. This may be,
in part, because Adalat CC is less bioavailable than the immediate release formulation.

Nifedipine is extensively metabolized to highly water
soluble, inactive metabolites accounting for 60% to 80% of the dose excreted in
the urine. Only traces (less than 0.1% of the dose) of the unchanged form can
be detected in the urine. The remainder is excreted in the feces in metabolized
form, most likely as a result of biliary excretion.

Nifedipine is metabolized via the cytochrome P450 3A4
system. Drugs that are known to either inhibit or induce this enzyme system may
alter the first pass or clearance of nifedipine.

No studies have been performed with Adalat CC in patients
with renal failure; however, significant alterations in the pharmacokinetics of
nifedipine immediate release capsules have not been reported in patients
undergoing hemodialysis or chronic ambulatory peritoneal dialysis. Since the
absorption of nifedipine from Adalat CC could be modified by renal disease,
caution should be exercised in treating such patients.

Because nifedipine is metabolized via the cytochrome P450
3A4 system, its pharmacokinetics may be altered in patients with chronic liver
disease. Adalat CC has not been studied in patients with hepatic disease;
however, in patients with hepatic impairment (liver cirrhosis) nifedipine has a
longer elimination half-life and higher bioavailability than in healthy
volunteers.

The degree of protein binding of nifedipine is high
(92%-98%). Protein binding may be greatly reduced in patients with renal or
hepatic impairment.

After administration of Adalat CC to healthy elderly men
and women (age > 60 years), the mean Cmax is 36% higher and the average
plasma concentration is 70% greater than in younger patients.

In healthy subjects, the elimination half-life of a
different sustained release nifedipine formulation was longer in elderly
subjects (6.7 h) compared to young subjects (3.8 h) following oral
administration. A decreased clearance was also observed in the elderly (348
mL/min) compared to young subjects (519 mL/min) following intravenous
administration.

Co-administration of nifedipine with grapefruit juice
results in up to a 2-fold increase in AUC and Cmax due to inhibition of CYP3A
related first-pass metabolism. Ingestion of grapefruit and grapefruit juice should
be avoided while taking nifedipine.

Clinical Studies

Adalat CC produced dose-related decreases in systolic and
diastolic blood pressure as demonstrated in two double-blind, randomized,
placebo-controlled trials in which over 350 patients were treated with Adalat CC
30, 60 or 90 mg once daily for 6 weeks. In the first study, Adalat CC was given
as monotherapy and in the second study, Adalat CC was added to a beta-blocker
in patients not controlled on a beta-blocker alone. The mean trough (24 hours
post-dose) blood pressure results from these studies are shown below:

Hemodynamics

Like other slow-channel blockers, nifedipine exerts a
negative inotropic effect on isolated myocardial tissue. This is rarely, if
ever, seen in intact animals or man, probably because of reflex responses to
its vasodilating effects. In man, nifedipine decreases peripheral vascular
resistance which leads to a fall in systolic and diastolic pressures, usually
minimal in normotensive volunteers (less than 5-10 mm Hg systolic), but
sometimes larger. With Adalat CC, these decreases in blood pressure are not accompanied
by any significant change in heart rate. Hemodynamic studies of the immediate
release nifedipine formulation in patients with normal ventricular function
have generally found a small increase in cardiac index without major effects on
ejection fraction, left ventricular end-diastolic pressure (LVEDP) or volume
(LVEDV). In patients with impaired ventricular function, most acute studies
have shown some increase in ejection fraction and reduction in left ventricular
filling pressure.

Electrophysiologic Effects

Although, like other members of its class, nifedipine
causes a slight depression of sinoatrial node function and atrioventricular
conduction in isolated myocardial preparations, such effects have not been seen
in studies in intact animals or in man. In formal electrophysiologic studies,
predominantly in patients with normal conduction systems, nifedipine
administered as the immediate release capsule has had no tendency to prolong
atrioventricular conduction or sinus node recovery time, or to slow sinus rate.